process fob the feefabamon of



chlol'ide-hydrochlorides.

med e5, 1941 2,235,862 rooooso eon THE r M INE-THIAZOLE M Mm & mom, New m rial No. 1937 c ll WI. 2%

lhjm invention relates to a process loc'the prepoi'otloh oi pyrimidine-thiazoic pounds, and more orticularly to the preparation od pyrimldli e-thlozole chloride-hydrochlorideo. object of the invention is the provision of o Simple and direct method ol premrloo ouch in which R1 and R: are alkyl radicals such es methyl, ethyl, propyl', etc and X is an onion. 7

have eott-neoritic properties and; ore useful in the treatment oi berl-beri, polyneuritis and other HGZ'YOUS diseases. The compound in which R11 cl Rn are methyl groups, and in which X 3 is chlorine, is the chloride hydrochloride of the the reaction product with silver chloride.

hhti-hehl'ltic vi B1.

Wiih B1 chloride hydrochloride has to synthesized by reacting 'l-methyl-5-B-hytlmn- 'el thiazole with Z-methyl-fi-oznino-h-bromoin which R is a radical. lt'h not practical to directly prepare salts of vitamin Euler example hy the reaction of fl-methyl-fi-amino fi-chlor methyl-pyrinndinohydrochloride with 4-1138)!!- fi-o-hwm-oxyethyl thiazole; because the E-ohlormethyl-Dyrimidine compound is diflicult to prepoi-e. v ilhove' discovered that vitamin B1 chloride hydrochloride may be easilyrmd directly obtained by condensing a thimle hydrochloride with a 7 member selected from the group oi a :l-oliwl-fi-amino-Ealkoxy-methyl-mimidine by .methyl-p yrimidine hydrochloridofl Such I. re; motion is a. surprising discovery, in that quota. hory ammonium salts V l have not heretofore'beeo preporedbyasimiiumethod, u

.Condeusatiodwith the hydro! compound is edectod withthelplimngoflol tvotor, and with the flkoxfwrimidine with the splitting oil of alcohoL The relation may be lmtobelimitedmfiy my, osflgmnr to .l., h corporation t mpllcatlon lela 16, 193%, he-

carried out in the presence or in the hbsence of -solvents, diiuents and/or condensation agents.

The following examples illustrate venous methods of carrying out the present invention,

but it is to he understood that these example are hy Way of illustrofion and not of limitation. hoomple l h cl li-methyl-fi-fl hydromethyl-thlooole hydrochloride and l 1 fi-hydmethyl-pdihe hydrochloride are heated to 158 C. with he. The ml. at first melts, hut after hhoht /2 hour, the m craduolly solidifies. it is heated for another hour, cooled, and dissolved in on small emoom of water. The solution thus obtained is tl'eogtcd with alcohol until the reoctlon product cmtah lizee. Upon recrystallization from aqueous aim hol, 4% ms. of pore vi B1 chloride hyolrm chloride, melting point 213 C2, is obtained.

Example ll me some. of Z-methyl-h-o o met-home methyl-pyrimidine hydrochloride and cm. at

"l-methyl-E-fl-hydroxy-ethyl-thiazole hydrochlo ride are heated with stirring for one hour on the oil bath at an oil-bath temperature of loll-Howl. The reaction mass is cooled, crystallized lrom absolute alcohol, and recrystallized from aqueous alcohol. Pure vi B1 chloride hydrochloride, on melting point 243? C.,ls ohtolned.

Example Hi 3m mo. of fi-methyl-ll-omino-h-ethom-meth- 'wi-pyrimieme-hydmemurloe and 1e o! lat methyl-E-o-hydzmm ethyl thiozole hydrochlotitle are heated on an oil bath for about one hour at NBS-rm C. The reaction mixture forms a clear melt, which gradually solidifis to a thick paste with the evolution of gas. The vitamin; B1 40 chloride hydrochloride recovered as in Example E. V

Modifications may be made without do from the spirit and scope oi? my invention. and I by the appended claims. Iclaim: 1. The process comprising condensing a thiacolehydrochloride with o comoo'und selected from the group co: or o. 2- 1w S-alkoiwmethflhyorlde, and so a-mi-e amino- 5]- hwdrthyl-pmmidine hydrochloride.

. of z-methm-h-g j lh amino-B-clkoxy-methyl pyrimidine hydrochloride, and 2-methyl-8-nmlno-5-hydroxymethylpyrimidine hydrochloride.

3. The process comprising condensing 4-methyl-ii-p-hydroxyethyl-thlazole hydrochloride with a compound selected from the group consisting o! z-met'hyi-d-unino 5 hydroxymethyl-pyrinnii. The process comp condensing a thi-l uole hydrochloride with fi-methyl-B-amino-S- methoxy-methyl-pyrimidine hydrhchloride.

"i. The process comprising condensing a. thiuolo hydrochloride with Z-methyl-d-amino-dethon-methyi-pyrimidine hydrochloride.

8. The process comprising condensing -methmamas yi-S-p-hydroxyethyl-thiazoh hydrochloride with a. B-methyi-G-amlno 5 alkoxy methyl-pyrimidine hydrochloride.

9. The process comprising condensing 4-methyl-5-p-hydroxyethyl-thiazole hydrochloride with Z-methyl-iianilnoefi methoxymethyl-pyrimidine hydrochloride.

10. The process comprising condensing 4- .methyl-5-p-hydroxyethyl-thiazole hydrochloride with 2-methyl-6-amino-5-ethoxymethyl-pyrimidine hydrochloride. I

11. The process comprising condensing a thiazoie hydrochloride with a 2-a1kyl-6-amino-5- hydroethyl-pyrimidine hydrochloride.

12. The process comprising condensing a thiozole hydrochloride 'with 2-methyl-6-amino-5- hydroethyl-dine hydrochloride.

13. The process comprising condensing 4- mefihyl-S-fi-hydroxyethyl-thiazole hydrochloride with 2-metlrvl-6-amlno-5-hydroxymethyl pyrimidine hydrochloride.

OTTO ZIMA. 

